Currently, the most commonly used botulinum neurotoxin—Botulinum neurotoxin type A (botulinum toxin type A). This neurotoxin is produced during fermentation in the presence of Clostridium botulinum strains.
In clinical practice, few drugs on the basis of botulinum toxin type A such as Botox (Botox), Dysport (Dysport), Kseomin (Xeomin) or Lantoks (Lantox) are used. There are a number of registered therapeutic applications for these drugs in a number of countries and there are therapeutic applications which are currently under developments and still not registered (Sheng-Chen, 2012, Toxins Clinical Uses of Botulinum Neurotoxins: Current Indications, Limitations and Future Developments, 4, 913-939). Documented applications by the US Food Drug Administration (FDA) include: in ophthalmology: treatment of strabismus; in neurology: treatment of blepharospasm, hemifacial spasm, spasmodic torticollis (cervical dystonia), chronic migraine (cranialgia), overactive detrusor, local muscle spasm in adults and children over 2 years old (including cerebral palsy and spasticity), axillary hyperhidrosis, hypersalivation; in aesthetic medicine: the elimination of facial wrinkles; in urology: treatment of the lower urinary tract disorders; in gastroenterology: treatment of the gastrointestinal tract disorders; in otolaryngology: treatment of spasmodic dysphonia.
Currently, the following applications of drugs based on botulinum toxin type A are under study: in dentistry: treatment of the temporomandibular joint dysfunction; in neurology: treatment of chronic musculoskeletal pain and diabetic neuropathy; in gynecology: treatment of vaginismus; in trauma and general surgery: improvement of wound healing; in cardiology: treatment of cardiac arrhythmias.
Cardiac arrhythmias are widespread and complex group of cardiac events. The only effective and rational surgical treatment of this disease is radiofrequency ablation (burning of arrhythmogenic areas of the heart using high frequency electric current). However, this method is not sufficiently effective (less than 60%) and has a high risk of complications such as hemopericardium, transesophageal fistula, post-ablation, atrial flutter, phrenic nerve paresis, mural thrombus and etc. in more than 30% of the cases (Camm et al., 2010, Guidelines for the management of atrial fibrillation European Heart Journal, 31, 2369-2429).
There are recent publications dedicated to the treatment of cardiac arrhythmias using botulinum neurotoxin, but the effects on the suppression of atrial fibrillation lasted no more than one week (Oh et al., 2011, Botulinum Toxin Injection in Epicardial Autonomic Ganglia Temporarily Suppresses Vagally Mediated. Atrial Fibrillation. Circ Arrhythm. Electrophysiol., 4, 560-565). The duration of this effect is not acceptable in clinical practice.
Currently, manufacturers of drugs based on botulinum toxin are involved in the development of the use of stabilizing agents such as various proteins, amino acids, polysaccharides, and other components to enhance the shelf life of the toxin and its effective delivery to the target organ.
Pharmaceutical compositions comprising a botulinum neurotoxin, selected from the various serotypes A, B, C, D, E, F or G and S botulinum, and polyamine acid, selected from the group comprising polylysine, polyarginine, polyhistidine or polyornithine have been developed (patent application RU 2011125775A; WO 2010/07842).
Other pharmaceutical compositions comprising a botulinum toxin type A in an amount from 6 pg to 30 ng with a biological activity of approximately 50-250 Units of LD50 (Lethal Dose, 50%), and additional components, such as buffer pH, excipient, diluent, cryoprotective agent and/or a stabilizer, selected from of hyaluronic acid, polyvinylpyrrolidone or polyethylene glycol have been developed (patent RU 2453333 C2, WO 2008/000490).
However, those known compositions do not have a prolonged action, nor increase the therapeutic effect of botulinum toxin and are not intended to treat cardiac arrhythmias. Those formulations have insufficient exposure in the tissues of the heart for optimal effect, and might have the rapid elimination of the active substance into the systemic circulation.
A liquid pharmaceutical composition comprising: (a) botulinum neurotoxin complex (type A, B, C, D, E, F or G) or high purity botulinum neurotoxin (type A, B, C, D, E, F or G) at concentration from 50 to 10,000 units LD50 per 1 ml solution, (b) a stabilizing agent comprising a surfactant (SAS), preferably polysorbate 80 in an amount from 0.005 to 0.02 vol. %, (c) sodium chloride as a crystalline agent in a concentration from 0.15 to 0.3 M, (d) a disaccharide, preferably sucrose, at a concentration 10-20 mM, (d) a buffer, mainly histidine, to maintain the pH 5.5-7.5 and water has been also developed (patent RU 2407541 C2, WO 2006/005910). However, those known compositions are not intended to treat disorders of cardiac rhythm, and there are said to induce stabilizing effects on botulinum toxin without any indications or suggestion of any prolonging action, or reduction of the therapeutic dose and side effects.
Therefore, there are important needs for new strategies of treatment of cardiac arrhythmias, in particular atrial fibrillation, which would lead to durable effects and would limit the potential side effects.